1. Dendritic Spine Density a Measure of Cognitive Reserve?
The cognitive reserve hypothesis is a heuristic concept used to explain apparent protection from
the onset of cerebral disease and/or cognitive decline in old age. This hypothesis explains the
disparity between clinical and pathological phenotypes and why, in two individuals with the
same extent of neuropathology, one may be demented while the other remains cognitively
intact.
Most neuroprotective agents are thought to exercise their action by promoting dendritic spine
growth. Although this is accomplished by different mechanisms, the neuroprotective power of
an agent can be assessed by its ability to increase dendritic spine density. Measuring dendritic
spine density in cultured neurons from patients with various neuropsychiatric conditions might
give us an idea of an individual’s cognitive reserve.
Neuropathological studies have demonstrated that a number of disease states, ranging from
schizophrenia to autism spectrum disorders, display abnormal dendritic spine morphology or
numbers. Moreover, recent genetic studies have identified mutations in numerous genes that
encode synaptic proteins, leading to suggestions that these proteins may contribute to aberrant
spine plasticity that, in part, underlie the pathophysiology of these disorders
http://www.ncbi.nlm.nih.gov/pubmed/18535839
A Software able to measure dendritic density:
Uncovering the mechanisms that regulate dendritic spine morphology has been limited, in the
past by the lack of efficient and unbiased methods for analyzing spines.
The discovery of automated 3D and 4D spine morphometry softwares, like Imaris, lead to the
ability of indirect measurement of cognitive capacity in the near future. The module Filament
Tracer, in the Imaris software can be used to automatically detect and measure spines across a
large dataset. This video explains how:
http://www.youtube.com/watch?v=9jQ0byergiw&feature=relmfu
Measuring Dendritic Spine Density in Cultured Neurons
Patient-specific neurons can be obtained by cellular reprogramming either via induced
pluripotent stem cells (IPSC) or more recently by lineage reprogramming (also called
transdifferentiation). The latter reprogramming method provides a fast route for creating
novel cell types and manufacturing functional tissues. TD enables the generation of
patient-specific cell types without the risk of creating potentially tumorigenic induced
pluripotent stem cells before differentiation. TD starts from fibroblasts and uses
“stemness factors” that are either microRNAs, transcription factors or both.

2. Once patient specific neurons have been created, they are allowed to form networks. On June 7,
2012, scientists at the UCSF-affiliated Gladstone Institutes have for the first time transformed
skin cells into cells that develop on their own into an interconnected, functional network of
brain cells. The next step could be determining dendritic spine density in neurons obtained by
transdifferentiation. This video illustrates the advantages of studying patient specific neurons.
http://www.youtube.com/watch?v=IU7iAf-YSFg
ADONIS SFERA, MD